Circulating tumor cells (CTCs) disseminate from the primary tumor and travel through the bloodstream and lymphatic system. The detection of and/or increase in the number of CTCs during a patient’s clinical course may be a harbinger of forthcoming overt metastasis. We aimed to examine the impact of 2 different surgical techniques, standard (ST) pancreaticoduodenectomy (PD) and no-touch isolation (NT) PD, on tumor behavior and outcome in patients with pancreatic cancer by using CTCs as biomarkers. In this pilot study, patients were randomized to either ST-PD (n = 6) or NT-PD (n = 6). Intraoperatively, blood samples were taken from the portal vein for measurement of CTCs before and immediately after removal of the tumor. An increase in CTCs was seen in 5 of 6 patients (83%) with ST-PD but no patients with NT-PD (P = .003). In the ST-PD and NT-PD groups, median overall survival was 13.0 and 16.7 months, respectively (P = .33); there was no difference in disease-free survival (P = .42). The use of NT-PD significantly reduced the number of CTCs in the portal vein with no benefit in survival outcomes compared with ST-PD, although more extensive studies are required.